Abstract Viral infection results in thousands of deaths and an enormous humanitarian burden every year, yet unlike antibiotics for bacterial infection, very few antivirals are available. At present, few methods exist for generating effective antivirals. The increasing availability of atomic resolution structural information of various viral surface proteins promises to chance this. The overall objective of this application is to use the surface glycoproteins of Paramyxoviruses (PMV) as a model system to generate design methodologies that will take advantage of structural features present in a broad range of viruses, resulting in a robust platform for the design of new therapeutics, diagnostics and immunogens for vaccination. PMVs are an ideal model system as their family members have the same fold for receptor recognition yet bind to very different host cell receptors. We recently demonstrated that computational protein design can be used to generate de novo antivirals that broadly neutralize diverse strains of influenza. These computer-generated proteins can also function as highly sensitive diagnostics. Guided by these results, the following specific aims will be pursued: (i) Develop general design strategies to target virus:host cell receptor interactions and design antivirals using Hendra and Nipah Viruses as model systems; (ii) inhibit membrane fusion of RSV by targeting the intermediate fusion states; and (iii) selectively stabilize the pre- and post-fusion state stabilization of the F- protein of RSV and probe their contributions to infectivity and vaccine design. The first aim is based on the observation that many receptor-binding sites of enveloped viruses lay within a recessed pocket, enabling evasion from the immune system. Computational design strategies which specifically target pockets will enable the development a robust algorithm to generate antiviral proteins which bind at these sites. The second aim is based on the hypothesis that the post-fusion structure of viral surface proteins provides the blueprint to targeting their transition state. Small proteins will be designed to molecularly ?jam? the 3-helical core structure that is common to most type I fusion proteins and therefore will be provide a general method to inhibit type I fusion proteins, which include viruses such as HIV-1, Ebola, SARS and others. Lastly, the objective of aim three is to simultaneously model the pre- and post-fusion states of the F-protein of RSV to generate variants to favor one state over the other. Variants will be assayed for changes in infectivity. The trapped pre-fusion state stabilized by disfavoring the post-fusion state will provide the basis for a new angle on immunogen design. If successful, data on designs will be fed back into the developed algorithm, leading to rapid development of new antivirals against emerging epidemics.